Pediatric bipolar disorder (BD) is a growing health problem, whose incidence has risen 40-fold in the past decade and now accounts for 20% of all children discharged from psychiatric hospitals. Of the current treatments for this burgeoning public health problem, virtually none are based on our understanding of the biology of pediatric BD. A growing body of research has shown that pediatric BD involves behavioral and brain alterations mediating cognitive flexibility-i.e., the ability to adapt one's thinking and behavior n response to changing rewards. This includes my own work showing that BD youths have behavioral and functional MRI neural alterations in reversal learning. THE PRIMARY OBJECTIVE of this R21/R33 Translational Novel Interventions grant application is to accelerate the translation of our data implicating brain/behavior alterations in reversal learning and cognitive flexibility in the pathophysiology of pediatric BD into a novel, mechanism-based, non-medication intervention using computer-assisted cognitive remediation for reversal learning (referred to as COGFLEX). OUR CENTRAL HYPOTHESIS is that COGFLEX will be feasible and acceptable for pediatric BD, given that others have shown similar interventions for related cognitive processes are a feasible, acceptable, and effective treatment component for adults with BD, unipolar depression, ADHD, and schizophrenia, and in children with ADHD. OUR RESEARCH METHOD: R21 PHASE: In collaboration with our cross-disciplinary team of experts in video game development, treatment development, cognitive remediation in children, pediatric BD, and biostatistics, we will refine our COGFLEX intervention, gather normative data for skill-building levels in 50 typically-developing children, and conduct a stage 1a open trial of the behavior, brain, and symptom effects of COGFLEX on 15 BD children. R33 PHASE: We will conduct a stage 1b randomized controlled trial of feasibility and acceptability in 40 pediatric BD participants, half randomized to receive the full COGFLEX intervention with 10 skill-building levels, and half receiving a control task (COGFLEX level 1 only). We will refine our intervention and submit an R01 application specifically designed and powered to test its efficacy for pediatric BD. SIGNIFICANCE: Our approach aligns with the objectives of PAR 11-177 and NIMH's strategies 3.1 Develop Novel Interventions and 1.4 RDoC project because we seek to develop a novel, mechanism-based non- medication intervention for pediatric BD, applying lessons learned from studies of observable behavior and neuroimaging-i.e., reversal learning. Thus, this project has the potential to transform the treatment for the NIMH high-priority area of pediatric BD by allowing critical refinements for a novel mechanism-based intervention. PUBLIC HEALTH RELEVANCE: Pediatric bipolar disorder (BD) is a growing health problem, whose incidence has risen 40-fold in the past decade and now accounts for 20% of all children discharged from psychiatric hospitals. Previously, we have shown that BD youths have brain and behavioral deficits underlying cognitive flexibility. Now, we will test the feasibility and acceptability of translating these findings into a new non-medication treatment using computers to train cognitive flexibility in BD youths.